Within the past decades the prevalence of obesity has risen in virtually all ethnic, racial and socioeconomic populations, in both genders and in all age groups. Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart diseases, hypertension and numerous other major illnesses and overall mortality from all causes. Therefore, weight reduction is critical for the obese patient. Thus there is impetus for creating new and alternative treatments for management of obesity.
Tesofensine, i.e. (1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane], first described in WO 97/30997, is a triple monoamine reuptake inhibitor in development for the treatment of obesity.
WO 2005/070427 describes the use of certain monoamine neurotransmitter re-uptake inhibitors for obtaining a sustained reduction of body weight. WO 2009/065845 describes the use of certain monoamine neurotransmitter re-uptake inhibitors for the treatment of over-eating disorders. WO 2009/080691 describes the use of certain monoamine neurotransmitter re-uptake inhibitors in a combination with additional anti-obesity agents for the treatment of obesity.
Tesofensine effectively produces a weight loss in obese individuals of about twice of that seen with currently marketed anti-obesity drugs. Results from clinical studies with Tesofensine also showed that the compound has a good safety profile and is well tolerated. However, though no clinically relevant cardiovascular adverse events or changes in either blood pressure or pulse were seen, some cardiovascular effects were measured with slight increases in heart rate and trends in blood pressure. Although such small effects have no immediate risk to the patient, some medical and regulatory concerns have been raised based on observational studies, that even small changes in cardiovascular parameters may have long term implications on patients' benefit/risk evaluation.
Preclinical and clinical data suggest that appetite suppression is an important mechanism by which Tesofensine exerts its robust weight reducing effect. Notably, the strong hypophagic response (i.e. less appetite, decreased feeding) to Tesofensine treatment is demonstrated to be linked to central stimulation of noradrenergic and dopaminergic neurotransmission. However, the sympathomimetic mode of action of Tesofensine may also associate with the elevated heart rate and blood pressure observed in clinical settings.
WO 2009/080693 describes pharmaceutical compositions comprising certain monoamine neurotransmitter re-uptake inhibitors in a combination with certain beta blockers, and WO 2011/100659 describes a method for ameliorating drug-induced elevation of blood pressure or increase in heartbeat by administration of an antihypertensive drug.
As such combination therapies seem tempting, drug combinations of Tesofensine with antihypertensive agents representing different mechanisms of action have been investigated. Based on these experiments it was found that some antihypertensive agents actually happen to interfere with the anti-obesity effects of Tesofensine, and thus are not suited for such combination therapy. Moreover, other antihypertensive agents are actually unable to reverse the increase in systolic blood pressure and heart rate induced by Tesofensine.
Metoprolol, i.e. 1-(Isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol, branded under various trade names, is a selective β1 (adrenergic) receptor blocker normally used in the treatment of various disorders of the cardiovascular system, and in particular hypertension.